title: CDDO-imidazolide induces DNA damage, G2/M arrest and apoptosis in BRCA1-mutated breast cancer cells.
abstract: Breast cancer-associated gene 1 (BRCA1) protein plays important roles in DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide, CDDO-Im) is a promising anticancer and chemopreventive agent with potent antiproliferative and apoptotic activities against a wide variety of cancer types. However, the mechanisms responsible for the selective apoptotic effects of CDDO-Im in cancer cells remain elusive. In the present work, CDDO-Im induced G2/M arrest and apoptosis in BRCA1-mutated mammary tumor cell lines. Prior to the induction of apoptosis, CDDO-Im induced DNA damage and the phosphorylation of H2AX followed by activation of the DNA damage response. Moreover, CDDO-Im also induced the generation of reactive oxygen species (ROS), which is associated with the induction of DNA damage, in both mouse and human tumor cells containing a BRCA1 mutation. The inhibition of ROS generation by uric acid prevented the induction of DNA damage by CDDO-Im. Furthermore, treatment with CDDO-Im did not induce ROS in nonmalignant MCF-10A breast epithelial cells or in E18-14C-27 breast cancer cells with wild-type BRCA1 genes and was not cytotoxic to normal mouse 3T3 fibroblasts, highlighting a selective therapeutic potential of CDDO-Im for BRCA1-associated breast cancer cells. Altogether, our results show that CDDO-Im induces ROS and subsequent DNA damage, thereby facilitating the activation of the DNA damage checkpoint, G2/M arrest, and finally apoptosis in BRCA1-mutated cancer cells. The particular relevance of these findings to the chemoprevention of cancer is discussed. Cancer Prev Res; 4(3); 425-34. ©2011 AACR.
authors.affiliation: Department of Pharmacology, Dartmouth Medical School, Hanover, NH, USA.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D019398:Genes, BRCA1; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; C029899:imidazole